Genetics and the pathobiology of aging serves as the integrating theme for three major areas of research in which somatic cell genetics and cell and tissue culture constitute the predominant methodologies. In project I, feasibility experiments will be carried out with cultivated mouse teratocarcinoma cells, the ultimate aim to use in-vitro mutagenesis and gene transfer to test the intrinsic mutagenesis hypothesis of senescence. The experiments will attempt to demonstrate in vitro gene transfer of a human gene (HPRT) to mouse teratocarcinoma cells and the expression of that gene in chimeric mice (via blastocyst injection) and their progeny. Project II employs a viral probe (encephalomyocarditis virus) as an in-vivo test (in post-replicative cells) of the error catastrophe theory of aging. In project III, we attempt to confirm and extend our recent finding of variegated translocation mosaicism in a progeroid patient (Werner's syndrome). The major long term goal is to discover which genetic loci are crucial in the specification of mammalian life-span and how such genes may modulate the phenotype of age-associated pathology.